The present invention concerns the testing for constituents of interest using radiation, preferably near infrared radiation. More particularly, an apparatus and a method of testing for constituents such as glucose, alcohol, drugs of abuse or other materials in a non-invasive manner have been developed. These methods are particularly well adapted for use in the home glucose testing market since they do not require a finger puncture to obtain a separable blood sample but rather can be utilized without bodily invasion.
Development of non-invasive testing method has become an important topic in the last several years. The spread of acquired immunodeficiency disease syndrome (AIDS), and the associated fear among public and healthcare personnel of AIDS has made many people afraid of invasive procedures. "Invasive procedures," as used herein are procedures where a sample such as blood is taken from the body by puncture or other entry into the body before analysis, while non-invasive procedures do not require bodily penetration. Not only can diseases such as AIDS be spread with invasive procedures if proper precautions are not followed, hepatitis and other similar blood diseases are more common problems in this type of testing. For example, a recent article, "Nosocomiel transmission of Hepatitis B virus associated with the use of a spring-loaded finger-stick device," New England Journal of Medicine 326 (11), 721-725 (1992), disclosed a mini-hepatitis epidemic in a hospital caused by the improper use of an instrument for taking blood samples. The nurses were unintentionally transmitting hepatitis from one patient to another with the sampling devise itself. This type of disease transfer is eliminated with non-invasive testing.
The diabetic population has also been clamoring for non-invasive test instruments. Many diabetics must test their blood glucose levels four or more times a day. The modern battery powered instruments for home use require a finger prick to obtain the sample. The extracted blood sample is then placed on a chemically treated carrier which is inserted into the instrument to obtain a glucose reading. This finger prick is painful and can be a problem when required often. In addition, although the price has dropped considerably on these instruments, the cost for the disposables and the mess and health risks associated with having open bleeding is undesirable.
Accordingly, a number of groups have recently tried to make non-invasive instruments for testing a variety of analytes, particularly glucose. A recent trend in non-invasive testing has been to explore the use of the near infrared spectral region (700-1100 nm). This region contains the third overtones for the glucose spectrum and eliminates many of the water bands and other inference bands that are potential problems for detection. However, this work has been carried out using classic spectrophotometric methods such as a set of narrow wavelength sources, or scanning spectrophotometers which scan wavelength by wavelength across a broad spectrum. The data obtained from these methods are spectra which then require substantial data processing to eliminate background; accordingly, the papers are replete with data analysis techniques utilized to glean the pertinent information. Examples of this type of testing includes the work by Clarke, see U.S. Pat. No. 5,054,487; and Primarily the work by Rosenthal et al., see e.g., U.S. Pat. No. 5,028,787. Although the Clarke work uses reflectance spectra and the Rosenthal work uses primarily transmission spectra, both rely on obtaining near infrared spectrophotometric data.
One problem with using these types of methods is that spectrophotometers were conceived primarily for accurate determination in terms of wavelength, of the spectral structure, rather than for discriminating the presence of weak broadband features in strong broadband backgrounds. Since in non-invasive testing for glucose and other materials the primary information sought is the concentration, those using spectrophotometric methods here had to resort to using a number of unsatisfactory analysis techniques to suppress unwanted interferences and to calculate the amplitude of the signal.
The Rosenthal U.S. Pat. No. 5,028,787 (the Rosenthal '787 Patent) illustrates this type of analysis technique for glucose testing using near infrared spectrophotometric methods.
First, a scan is made of 10 gl/.sub.I vs. wavelength and the raw data is analyzed. FIG. 1 of the present application is just such a plot, taken from the Rosenthal '787 Patent. Rosenthal takes the data developed from this scan and analyzes it using first and second derivative equations in an attempt to obtain meaningful information. Additional patents and articles by Rosenthal, Cavinato, and others have used similar techniques for determinations of levels of fat, ethanol, and other constituents of interest in a variety of samples.
However, all these techniques are dependent on the discrimination of the spectrophotometric data obtained. No form of data analysis can add to the initial information gathered; it can only put the measured information in a form which deemphasizes certain items of interference arising from the background or other constituents which make analysis of the sample difficult. A better solution to the problems of interference in broadband spectra is rather to obtain different raw data by measuring different aspects of the phenomenon.
As noted, FIG. 1 is a plot of 10gl/.sub.I vs. wavelength, taken using a scanning spectrophotometer. The scanning spectrophotometer takes a series of discrete, single wavelength intensities and presents them as a function of time to obtain the spectrum. A plurality of high resolution features are necessary to obtain meaningful information. However, the spectra of analytes of present interest do not include the large high resolution structures of classical infrared spectroscopy but rather have a few low resolution features with much of the information contained in the intensity. As such, these spectra appear more like the reflection spectra of colored objects in the visible region. A detection device optimized for analysis of this type of spectra would provide better discrimination.
Human vision is a incompetent spectrophotometer but is superb at the subtlest color discrimination and identification even under greatly varying illumination. The present invention measures or obtains the raw data in the infrared in a manner more similar to the way the eye Performs in the visible, than classic spectrophotometric measurements. While visual perception is very complex and not completely understood, one approach suggested is the obtaining and processing of the raw data as closely as possible to the known aspects of color perception, utilizing a succession of steps or processing levels. Each step itself provides a useful product and succeeding steps represent products of greater capability.
The first step is the analog of colorimetry. Colorimetry is numerical color communication. This numeric approach uses three dimensions to describe the color. There presently are several such three dimensions spaces in use. One of these three dimensional spaces is the CIE 1931 (x,y)-chromaticity diagram (See FIG. 2). Luminosity, the third dimension, is not shown in FIG. 2. It is the trivariant nature of color vision that permits color to be specified in a three dimensional space.
Another three dimensional space is represented in FIG. 3. A plot is made of hue, chroma and value and is shown as a three dimensional solid. These three numerical values can be used to specify any perceived color.
It is most important to note that although it is convenient to describe color in terms of a colorimetry, this is not color perception. Color perception is much more complex. However colorimetry is useful for color matching under specific conditions. An analog of colorimetry, particularly one in the infrared region, would show similar usefulness in determining analyte concentration.
There are commercially available colorimeters in the visible for measuring tristimulus values in terms of luminosity, hue and saturation. Briefly, these colorimeters use three detectors, with each detector input being filtered with a different filter function. Each of the filter functions is chosen to be similar to the three absorption spectra of the pigments of the three color receptive cones of the human retina. However, it appears no one has used, or even considered the use, of an analog of color perception for concentration measurements or even applied the method of colorimetry to infrared measurements as described herein.
Similarly, noninvasive measurement of arterial oxygen saturation by pulse oximetry is widely acknowledged to be one of the most important technological advances in clinical patient monitoring. Pulse oximeters measure differences in the visible and near infrared absorption spectra of fully oxygenated and reduced hemoglobin in arterial blood. Unlike clinical blood gas analyzers, which require a sample of blood from the patient and can only provide intermittent measurement of patient oxygenation, pulse oximetry provide continuous, and instantaneous measurement of blood oxygen levels.
However, current commercial oximeters, and their algorithms are inaccurate under conditions of low pulse pressure and/or low oxygen saturation. These severe conditions are observed in the normal unborn fetus. Unlike the transmission sampling of the commercial oximeters, space limitations associated with the fetus require that the spectral data be obtained by reflectance sampling. Reflectance sampling results in spectral data with a significantly lower signal-to-noise ratios than obtained with transmission sampling. It has been suggested that a new analysis technique using multivariate calibration methods can improve the precision, accuracy and reliability of quantitative spectral analysis. Even these techniques are limited by the type of input data.
Accordingly, an object to the invention is to provide an apparatus which provides an analog of colorimetric detection units so as to allow the measurements of the concentration of a constituent of interest.
Another object of the invention is to provide a method of measuring constituents of interest in a sample, preferably in a non-invasive manner, which is accurate, inexpensive and quick using an analog of a colorimetric analysis.
Another method of the invention is to provide a handheld instrument for glucose or drugs of abuse measurement based on the application of colorimetric type measurements to the near infrared region.
These and other objects and features will be apparent from the description and the accompanying drawing.